Sj"gren's syndrome is the second most common form of autoimmune disease in North America and Europe. Most malignant lymphomas of the salivary gland are classified as low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type, and arise in the background of a benign lesion known as lymphoepithelial sialadenitis (LESA) which is universally present in all patients with Sj"gren's syndrome. In effect the LESA is the histopathological manifestation of Sj"gren's syndrome. The deregulated molecular pathways involved in the transition from LESA to salivary MALT are unknown. Accordingly, in this application, we propose to utilize a mass spectrometry-based proteomics strategy potentiated by sophisticated bioinformatics-driven pathway analyses to uncover the underlying molecular pathway deregulation underlying the development of salivary MALT from LESA/Sj"gren's syndrome. In Specific Aim 1, we will perform global quantitative proteomic analysis in an unbiased fashion and compare the profiles of LESA and salivary MALT lymphoma to determine the most significant proteomic changes involved in the transition from LESA to salivary MALT lymphoma. In Specific Aim 2, we will construct the deregulated pathway networks that occur in LESA to salivary MALT lymphoma based on the quantitative proteomic data obtained from MS/MS experiments performed in Specific Aim 1. In Specific Aim 3, we will functionally interrogate the central proteins in the deregulated signaling networks involved in development of salivary MALT by investigating the cellular effects of ectopic expression of selected deregulated proteins. In Specific Aim 4, we will disseminate the data obtained by quantitative MS/MS to all users using tools that we have developed to archive and distribute MS data for further interrogation. Our studies employing large-scale identification of quantitative changes in protein expression that accompany the transition of LESA to salivary MALT will elucidate the pathogenetically-relevant deregulated pathways and identify susceptible elements in the deregulated pathways that may facilitate the diagnosis of salivary MALT lymphoma, and may be targeted for salivary MALT therapy. Our studies have broad implications for the potential of quantitative mass spectrometry-based approaches for the investigation of the development of all forms of cancer. Project Narrative: The biologic alterations underlying the pathogenesis of salivary MALT lymphomas are unknown. Our studies will identify the pathogenetically relevant pathways that are deregulated in the progression of Sj"gren's syndrome to salivary MALT lymphoma. Importantly, our studies will reveal protein biomarkers by which this disease may be reliably diagnosed, and distinguished from benign lymphoid proliferations of the salivary gland and other low-grade B-cell lymphomas. Identification of the deregulated pathways will also provide opportunities for the development of novel therapies that target the underlying pathogenetic abnormalities that occur in salivary MALT lymphoma.